Murine models of hematopoietic stem cell transplantation will be utilized to investigate the association between advancing age and more severe graft-vs.-host disease (GVHD). The long-term objective of this work is to understand the pathophysiology of GVHD in aged transplant recipients and thereby to develop interventions which will decrease the risk of severe GVHD and increase the applicability of hematopoietic stem cell transplantation in aging recipients. The specific aims of this work are (1) to determine whether the increased severity of GVHD in older mice is caused by greater intestinal tissue injury resulting in enhanced translocation of endotoxins and subsequent release of proinflammatory cytokines and (2) to determine whether the association of more severe GVHD with advancing age of the recipient holds true both for H2 class II antigen- mediated GVHD and for H2 class I antigen-mediated GVHD. In order to test the hypothesis that more severe GI tract damage due to conditioning therapy will lead to more severe GVHD, clinical GVHD scores, serum endotoxin and TNF-alpha levels, GI tract and liver histopathology, and survival will be assessed in a well characterized hematopoietic stem cell transplantation model (C57BU6 -+ B6D2F1). Endotoxin and TNF-alpha blockers will be employed in vivo to test the hypothesis that interruption of the proinflammatory cytokine cascade will decrease GVHD morbidity and mortality in aged animals. Finally, to test the hypothesis that the association of advancing age with more severe GVHD is primarily due to GI tract damage and is independent of the type of T cell effector, both CD4-mediated and CD8-mediated models of GVHD will be evaluated for the effects of aging upon GVHD scores, GI tract and liver histopathology, serum TNF-alpha levels, and survival.